Inhibition of the MDR-1 gene product and drug transporter P-glycoprotein (P-gp) is a potential cause of drug interactions in HIV infected patients. HIV protease inhibitors (PIs) inhibit P-gp and may increase the blood levels of co-administered medications. However, controlled studies examining the influence of PIs on P-gp transport have not been investigated in humans. To characterize the influence of the protease inhibitor ritonavir (RTV) on the pharmacokinetics of digoxin (including renal clearance), twelve healthy subjects will receive a single 0.4 mg digoxin dose before, and during/after 15 days of ritonavir 200 mg twice daily. An 11-day washout period will precede RTV administration. Blood and urine will be collected and sampled for digoxin, and digoxin pharmacokinetic parameter values will be determined pre- and post ritonavir and compared. To date, data are available for 6 subjects who have completed this study. In accordance with what was expected, RTV significantly increased the blood levels of digoxin by 48%. All 6 subjects experienced an increase in digoxin exposure with RTV; this increase was marked (29-67%) in 5/6 subjects. Preliminary results from this investigation suggest that RTV increases the blood levels of digoxin. These results are consistent with RTV-mediated inhibition of P-gp although other drugs transporters may also be involved. P-gp modulation by protease inhibitors such as RTV may be an under-recognized mechanism by which these drugs interact with concurrent medications.